The goal of our preclinical studies for cancer treatment are currently focused on preclinical evaluation of combination therapy with two drugs, rapamycin (mTOR inhibitor) and MS-275 (HDAC, histone deactylase inhibitor) which interact with the two signal transduction pathways, RB and PI3K. These drugs have been evaluated in tissue culture cell lines for the following cancers: multiple myeloma, plasmacytoma or plasma cell tumors, and mantle cell lymphoma.Combined treatment with low concentrations of MS-275 and rapamycin resulted in a synergistic effect on growth inhibition in vitro and in vivo. Rapamycin decreased phosphorylation of S6, and MS-275 increased acetylation of histone H3 and H4. Both effects were further accentuated by the combination treatment. Both drugs caused cell cycle arrest, via different signaling events; MS-275 induced the expression of p21, p27 and p16, whereas rapamycin reduced the expression of cyclin D and p21. In contrast to rapamycin alone, the combination treatment did not lead to MAPK or AKT activation. MS-275 and rapamycin increased, and their combination further enhanced, the expression of pro-apoptotic proteins Foxo and Bim, and decreased expression of the pro-survival protein Survivin. The therapeutic potential of the combination was supported by in vivo studies of MM xenografts. As a direct result of these studies, we screened small molecule arrays to look for direct inhibitors of MYC.